It has become apparent that a change in the protein concentration will modulate the elimination of drugs not only through changes in the unbound fraction of drug in serum but also through an additional "protein effect". This "protein effect" varies among drugs. The mechanisms involved have not been established, although several theories have been put forward. If changes in the protein concentration can also affect the unbound concentration -- response relationship is, on the other hand, not established. The specific aim of this project is to elucidate the mechanism(s), responsible for the "protein effect" and to determine its significance. The studies will focus on determining the effect of the two main drug binding proteins in serum, albumin and alpha-1-acid glycoprotein. The mechanisms responsible for modulating the metabolism of drugs will be determined using the isolated rat liver perfusion preparation. The unbound concentration-response relationship measurements will be carried out in the isolated perfused guinea pig heart. Test drugs to be studied will be primarily antiarrhythmic and antihypertensive agents. Answers to the following questions will be sought: 1) Do protein concentration changes alter the unbound concentration-response relationship? 2) Do the plasma proteins interact with specific protein receptors? 3) Is the interaction non-specific? 4) Will interaction of albumin with alpha-1-acid glycoprotein enhance or decrease the "protein effect"? 5) Is the effect direct or indirect? 6) Is the effect occurring at the cellular level or is it related to the hepatic architecture? 7) Is the effect qualitatively and quantitatively different for high and low extraction ratio compounds? The results of the proposed studied will provide new insight into our understanding of serum proteins as they relate to the response and elimination of cardiovascular drugs, and will assist in optimizing drug delivery to the cardiac patient by improving our ability to assess the impact of protein changes in disease state on this class of drugs.